Significant progress was made on this research project during this reporting period. 1) we have recently reported that both the cannabinoids 9-tetrahydrocannabinol (9-THC) and WIN55,212-2, produced biphasic effects on brain reward function mild enhancement of brain-stimulation reward (BSR) at low doses, but inhibition at higher doses. Pretreatment with a CB1 receptor antagonist (AM251) attenuated the low dose-enhanced BSR, while a CB2 receptor antagonist (AM630) attenuated high dose-inhibited BSR. To confirm these opposing effects, rats were treated with selective CB1 and CB2 receptor agonists. These compounds produced significant BSR enhancement and inhibition, respectively. These findings suggest that CB1 receptor activation produced reinforcing effects, whereas CB2 receptor activation was aversive. The subjective effects of cannabis depend on the balance of these opposing effects. These findings well explain why cannabis can be either rewarding, ineffective, or aversive in humans, as expression of CB1 and CB2 receptors may differ in the brains of different subjects. 2) Although growing evidence indicates the presence of functional CB2Rs in the brain, this finding is disputed by the specificity of CB2R antibody signals in some studies. To fully address this issue, we have recently used two strains of currently available partial CB2-knockout (CB2-KO) mice as controls, four anti-rat or anti-mouse CB2R antibodies in both Western and IHC assays. We found that none of the tested four polyclonal antibodies are absolutely mouse CB2R-specific. Their non-specific binding may be related to the expression of mutant or truncated CB2R-like proteins in partial CB2-KO mice and the use of anti-rat CB2 antibodies to detect mouse brain CB2Rs because the epitopes are different between rat and mouse CB2Rs. 3) We have recently reported that activation of CB2Rs reduces VTA dopamine (DA) neuron excitability. However, the molecular mechanisms underlying this action are poorly understood. Using cell-attached recording in VTA slices, we found that CB2Rs modulate VTA DA neuron excitability mainly through intracellular cAMP-PKA system that activates M-type K+ currents. 4) A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently FDA-approved medication for epilepsy, in treatment of many other neuropsychological disorders. Recently, we examined the effects of CBD on oral sucrose self-administration in rodents and the underlying receptor mechanisms using CB1- and CB2-KO mice as controls. We found that systemic administration of CBD inhibits sucrose self-administration likely by CB1 receptor antagonism and CB2 receptor agonism. This finding suggests that CBD may have therapeutic potential in reducing binge eating and the development of obesity. 5) As mentioned above, clinical trials with CB1R antagonists/inverse agonists such as SR141716A (rimonabant) for the treatment of obesity and drug addiction failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recently, we explored the potential utility of a neutral CB1R antagonist (AM4113), which has no inverse agonist profile, for the treatment of opioid or psychostimulant use disorder. We found that AM4113 is similarly effective as rimonabant in attenuation of heroin, but not cocaine or methamphetamine, self-administration. But unlike rimonabant that dose-dependently inhibits the brain reward function by itself, but AM4113 had no effect on brain-stimulation reward, suggesting that rimonabant may produce aversive effects while AM4113 may not. These findings suggest that neutral CB1R antagonists such as AM4113 deserve further research as a new class of CB1R-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.